tbuckley/cabot-search huggingface dataset:
Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure
Authors: Arpan G. Mazumder, Amélie M. Julé, Daniel Sun
Journal: Molecular Neurodegeneration (2023)

The optic nerve is an important tissue in glaucoma and the unmyelinated nerve head region remains an important site of many early neurodegenerative changes. In both humans and mice, astrocytes constitute the major glial cell type in the region, and in glaucoma they become reactive, influencing the optic nerve head (ONH) microenvironment and disease outcome. Despite recognizing their importance in the progression of the disease, the reactive response of optic nerve head astrocytes remains poorly understood.To determine the global reactive response of ONH astrocytes in glaucoma we studied their transcriptional response to an elevation in IOP induced by the microbead occlusion model. To specifically isolate astrocyte mRNA in vivo from complex tissues, we used the ribotag method to genetically tag ribosomes in astrocytes, restricting analysis to astrocytes and enabling purification of astrocyte-associated mRNA throughout the entire cell, including the fine processes, for bulk RNA-sequencing. We also assessed the response of astrocytes in the more distal myelinated optic nerve proper (ONP) as glaucomatous changes manifest differently between the two regions.Astrocytes of the optic nerve exhibited a region-specific and temporally distinct response. Surprisingly, ONH astrocytes showed very few early transcriptional changes and ONP astrocytes demonstrated substantially larger changes over the course of the experimental period. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as highly upregulated processes in both ONH and ONP astrocytes, with the former showing additional upregulation in antioxidative capacity and proteolysis. Interestingly, optic nerve astrocytes demonstrated a limited neuroinflammatory response, even when challenged with a more severe elevation in IOP. Lastly, there were a greater number of downregulated processes in both astrocyte populations compared to upregulated processes.Our findings demonstrate an essential role for energy metabolism in the response of optic nerve astrocytes to elevated IOP, and contrary to expectations, neuroinflammation had a limited overall role. The transcriptional response profile is supportive of the notion that optic nerve astrocytes have a beneficial role in glaucoma. These previously uncharacterized transcriptional response of optic nerve astrocytes to injury reveal their functional diversity and a greater heterogeneity than previously appreciated.
Early intervention for depressive symptoms in multiple sclerosis
Authors: Litza Kiropoulos
Journal: The Lancet Digital Health (2023)

In-person cognitive behavioural therapy (CBT)-based interventions have been used successfully to treat depressive symptoms in people with multiple sclerosis,1 including the use of internet-based CBT (iCBT) interventions over the past 13 years. In The Lancet Digital Health, Stefan M Gold and colleagues2 describe a parallel-group trial of an iCBT programme for this purpose. The programme—which includes ten modules and a summary module, each featuring conversational text passages and multiple response options—was effective in reducing depressive symptoms at post-assessment, as measured by the Beck Depression Inventory-II, both in patients using the therapist-guided format (d=0·96) and in those using the stand-alone format (d=0·97) of the programme compared with a treatment-as-usual control group, with reductions being maintained at 12-month follow up.
FAIR, ethical, and coordinated data sharing for COVID-19 response: a scoping review and cross-sectional survey of COVID-19 data sharing platforms and registries
Authors: Lauren Maxwell, Priya Shreedhar, Delphine Dauga, Peter McQuilton, Robert F Terry, Alisa Denisiuk, Fruzsina Molnar-Gabor, Abha Saxena, Susanna-Assunta Sansone
Journal: The Lancet Digital Health (2023)

Data sharing is central to the rapid translation of research into advances in clinical medicine and public health practice. In the context of COVID-19, there has been a rush to share data marked by an explosion of population-specific and discipline-specific resources for collecting, curating, and disseminating participant-level data. We conducted a scoping review and cross-sectional survey to identify and describe COVID-19-related platforms and registries that harmonise and share participant-level clinical, omics (eg, genomic and metabolomic data), imaging data, and metadata. We assess how these initiatives map to the best practices for the ethical and equitable management of data and the findable, accessible, interoperable, and reusable (FAIR) principles for data resources. We review gaps and redundancies in COVID-19 data-sharing efforts and provide recommendations to build on existing synergies that align with frameworks for effective and equitable data reuse. We identified 44 COVID-19-related registries and 20 platforms from the scoping review. Data-sharing resources were concentrated in high-income countries and siloed by comorbidity, body system, and data type. Resources for harmonising and sharing clinical data were less likely to implement FAIR principles than those sharing omics or imaging data. Our findings are that more data sharing does not equate to better data sharing, and the semantic and technical interoperability of platforms and registries harmonising and sharing COVID-19-related participant-level data needs to improve to facilitate the global collaboration required to address the COVID-19 crisis.
Contemporary Use and Implications of Beta-Blockers in Patients With HFmrEF or HFpEF
Authors: Alexander Peikert, Bradley A. Bart, Muthiah Vaduganathan, Brian L. Claggett, Ian J. Kulac, Mikhail N. Kosiborod, Akshay S. Desai, Pardeep S. Jhund, Carolyn S.P. Lam, Silvio E. Inzucchi, Felipe A. Martinez, Rudolf A. de Boer, Adrian F. Hernandez, Sanjiv J. Shah, Magnus Petersson, Anna Maria Langkilde, John J.V. McMurray, Scott D. Solomon, Orly Vardeny
Journal: JACC Heart Failure (2023)

While beta-blockers are not recommended for the treatment of HFpEF according to the latest ESC and AHA/ACC/HFSA guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers might adversely influence clinical outcomes by limiting chronotropic response in HFpEF. To examine the contemporary use and implications of beta-blockers in patients with HFmrEF or HFpEF. In the DELIVER trial, a total of 6,263 patients with symptomatic HF with LVEF >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF. Overall, beta-blockers were used in 5,177 patients (83%) with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR 0.70 [95% CI 0.60-0.83]). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR 0.82 [95% CI 0.72-0.94]) and those not taking beta-blockers (HR 0.79 [95% CI 0.61-1.03]; Pinteraction=0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use. In patients with HFmrEF or HFpEF enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use.
Erucic acid improves the progress of pregnancy complicated with systemic lupus erythematosus by inhibiting the effector function of CD8<sup>+</sup> T cells
Authors: Yanling Chang, Meng Jiang, You Wang, Qiong Fu, Sihan Lin, Jiayue Wu, Wen Di
Journal: MedComm (2023)

Abstract Pathogenic CD8 + T cells are pivotal contributors to the onset of systemic lupus erythematosus (SLE). Erucic acid (EA) has been proven to have anti‐inflammatory activity. However, the capacity of EA to regulate pathogenic CD8 + T cells in the context of pregnancy complicated with SLE (pSLE) remains unclear. In our investigation, we observed augmented CD8 + T cell effector function juxtaposed with diminished EA levels in pSLE patients relative to healthy pregnant controls. Significantly, plasma EA levels exhibited a negative correlation with the severity of pSLE‐associated complications. In blood from patients with pSLE, EA inhibited the effector function of CD8 + T cells, concurrently dampening the maintenance of stem cell‐like memory CD8 + T cells. Mechanistically, EA orchestrated the inhibition of CD8 + T cell effector function by impeding signal transducer and activator of transcription 3 phosphorylation and promoting ferroptosis. Moreover, EA supplementation in pregnant MRL/lpr mice manifested as the attenuation of uterine CD8 + T cell effector function, culminating in the mitigation of placental pathological damage. Our findings uncover the immune response modulatory effects of EA upon pathogenic CD8 + cells, thereby unveiling new perspectives for therapeutic strategies targeting pSLE patients.
Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology
Authors: Mingjie Jiang, Zhongyuan Yang, Juanjuan Dai, Tong Wu, Zan Jiao, Yongchao Yu, Kang Ning, Weichao Chen, Ankui Yang
Journal: MedComm (2023)

Abstract The polymorphic microbiome has been proposed as a new hallmark of cancer. Intratumor microbiome has been revealed to play vital roles in regulating tumor initiation and progression, but the regulatory mechanisms have not been fully uncovered. In this review, we illustrated that similar to other components in the tumor microenvironment, the reside and composition of intratumor microbiome are regulated by tumor cells and the surrounding microenvironment. The intratumor hypoxic, immune suppressive, and highly permeable microenvironment may select certain microbiomes, and tumor cells may directly interact with microbiome via molecular binding or secretions. Conversely, the intratumor microbiomes plays vital roles in regulating tumor initiation and progression via regulating the mutational landscape, the function of genes in tumor cells and modulating the tumor microenvironment, including immunity, inflammation, angiogenesis, stem cell niche, etc. Moreover, intratumor microbiome is regulated by anti‐cancer therapies and actively influences therapy response, which could be a therapeutic target or engineered to be a therapy weapon in the clinic. This review highlights the intratumor microbiome as a vital component in the tumor microenvironment, uncovers potential mutual regulatory mechanisms between the tumor microenvironment and intratumor microbiome, and points out the ongoing research directions and drawbacks of the research area, which should broaden our view of microbiome and enlighten further investigation directions.
Systematic review of deep learning image analyses for the diagnosis and monitoring of skin disease
Authors: Shern Ping Choy, Byung Jin Kim, Alexandra Paolino, Wei Ren Tan, Sarah Man Lin Lim, Jessica Seo, Sze Ping Tan, Luc Francis, Teresa Tsakok, Michael Simpson, Jonathan N. W. N. Barker, Magnus D. Lynch, Mark S. Corbett, Catherine H. Smith, Satveer K. Mahil
Journal: npj Digital Medicine (2023)

Skin diseases affect one-third of the global population, posing a major healthcare burden. Deep learning may optimise healthcare workflows through processing skin images via neural networks to make predictions. A focus of deep learning research is skin lesion triage to detect cancer, but this may not translate to the wider scope of >2000 other skin diseases. We searched for studies applying deep learning to skin images, excluding benign/malignant lesions (1/1/2000-23/6/2022, PROSPERO CRD42022309935). The primary outcome was accuracy of deep learning algorithms in disease diagnosis or severity assessment. We modified QUADAS-2 for quality assessment. Of 13,857 references identified, 64 were included. The most studied diseases were acne, psoriasis, eczema, rosacea, vitiligo, urticaria. Deep learning algorithms had high specificity and variable sensitivity in diagnosing these conditions. Accuracy of algorithms in diagnosing acne (median 94%, IQR 86-98; n = 11), rosacea (94%, 90-97; n = 4), eczema (93%, 90-99; n = 9) and psoriasis (89%, 78-92; n = 8) was high. Accuracy for grading severity was highest for psoriasis (range 93-100%, n = 2), eczema (88%, n = 1), and acne (67-86%, n = 4). However, 59 (92%) studies had high risk-of-bias judgements and 62 (97%) had high-level applicability concerns. Only 12 (19%) reported participant ethnicity/skin type. Twenty-four (37.5%) evaluated the algorithm in an independent dataset, clinical setting or prospectively. These data indicate potential of deep learning image analysis in diagnosing and monitoring common skin diseases. Current research has important methodological/reporting limitations. Real-world, prospectively-acquired image datasets with external validation/testing will advance deep learning beyond the current experimental phase towards clinically-useful tools to mitigate rising health and cost impacts of skin disease.
Modified Single Port Laparoscopic Peritoneal Dialysis Catheter Insertion - Initial Experience and Outcome from a Tertiary Care Centre
Authors: Suhail Khuroo, Ajaz Ahmed Wani, Bharti ., Deepak Sharma, Deepak Pathania, Farzana Feroze, Hitesh Gupta, Suhail Khuroo
Journal: International Journal of Surgery (2023)

Background: Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are emerging as a major health related issues in developing countries. The increasing numbers require rapid adaptation of existing health-care policies. The number of patients requiring renal care is only bound to increase in coming years with the increasing incidence and prevalence of diabetes. Continuous ambulatory peritoneal dialysis (CAPD) catheter placement is performed on end-stage renal disease (ESRD) patients. There is abundant literature regarding post-operative outcomes and re-operative rates following CAPD. We report our initial experience of modified single port laparoscopic technique of placing CAPD catheters using a single port through the Palmer’s point and discuss our surgical outcomes. Methods: This was a retrospective review (2019-2020) of patients undergoing CAPD catheter placement at SMVD Narayana Superspecialty Hospital. Outcome analysis focused on patient related outcomes, including early (&lt; 30 days) versus late (≥ 30 days) complication and re-operation rates. Results: A total of 30 patients with ESRD, (mean ASA score = 3.3) were included in the study who underwent modified single port laparoscopic (n = 30) CAPD catheter placement (mean follow-up = 180 days). The total complication rate with the procedure was 43%, with re-operation rate of 20%. CAPD catheter non-function occurred in 06 patients (20% of total). CAPD catheter migrations occurred in 03 patients (10% of total). CAPD catheter related infections occurred in 05 patients (16% of total), and 02 required re-operation; 03 patients were treated successfully with culture directed antibiotics. There were 2 deaths during the study period, one due to peritonitis and other due to underlying cardiac disease. There was no surgical mortality in the study group. Conclusion: Although CAPD catheter placement in patients with ESRD are technically un-complicated to accomplish, long term results suggest as many as one in three patients will struggle with some form of catheter malfunction or infection. Our modified technique and the results have led to changes in our CAPD catheter placement technique, as well as the post-operative patient care algorithm.
Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice
Authors: Wei Cheng, Jing Huang, Xiu-Qing Fu, Wei-Ya Tian, Peng-Ming Zeng, Yang Li, Zhen-Ge Luo
Journal: Molecular Therapy (2023)

Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1
The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposals for the N and the M Components for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors
Authors: Wentao Fang, Nicolas Girard, Vanessa Cilento, Emily Goren, Daniel Dibaba, Enrico Ruffini, Usman Ahmad, Sarit Appel, Andrea Bille, Souheil Boubia, Cecilia Brambilla, Ayten Kayi Cangir, Frank Detterbeck, Conrad Falkson, Pier Luigi Filosso, Giuseppe Giaccone, Francesco Guerrera, James Huang, Maurizio Infante, Dong Kwan Kim, Marco Lucchi, Mirella Marino, Edith M. Marom, Andrew G. Nicholson, Meinoshin Okumura, Ramon Rami-Porta, Andreas Rimner, Charles B. Simone, Hisao Asamura
Journal: Journal of Thoracic Oncology (2023)
Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy
Authors: Boaz Wong, Anabel Bergeron, Glib Maznyi, Kristy Ng, Anna Jirovec, Harsimrat K. Birdi, Daniel Serrano, Marcus Spinelli, Max Thomson, Zaid Taha, Akram Alwithenani, Andrew Chen, Ian Lorimer, Barbara Vanderhyden, Rozanne Arulanandam, Jean-Simon Diallo
Journal: Molecular Therapy (2023)

The clinical efficacy of VSVΔ51 oncolytic virotherapy has been limited by tumor resistance to viral infection, so strategies to transiently repress antiviral defenses are warranted. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor currently being tested in clinical trials for its antitumor potential. In this study, we demonstrate that pevonedistat sensitizes human and murine cancer cells to increase oncolytic VSVΔ51 infection, increase tumor cell death, and improve therapeutic outcomes in resistant syngeneic murine cancer models. Increased VSVΔ51 infectivity was also observed in clinical human tumor samples. We further identify the mechanism of this effect to operate via blockade of the type 1 interferon (IFN-1) response through neddylation-dependent interferon-stimulated growth factor 3 (ISGF3) repression and neddylation-independent inhibition of NF-κB nuclear translocation. Together, our results identify a role for neddylation in regulating the innate immune response and demonstrate that pevonedistat can improve the therapeutic outcomes of strategies using oncolytic virotherapy.
Contact lens as an emerging platform for ophthalmic drug delivery: A systematic review
Authors: Hongyu Yang, Ming Zhao, Dandan Xing, Jian Zhang, Ting Fang, Faxing Zhang, Zhihao Nie, Yaming Liu, Lihua Yang, Ji Li, Dongkai Wang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

The number of people with eye diseases has increased with the use of electronics. However, the bioavailability of eye drops remains low owing to the presence of the ocular barrier and other reasons. Although many drug delivery systems have been developed to overcome these problems, they have certain limitations. In recent years, the development of contact lenses that can deliver drugs for long periods with high bioavailability and without affecting vision has increased the interest in using contact lenses for drug delivery. Hence, a review of the current state of research on drug delivery contact lenses has become crucial. This article reviews the key physical and chemical properties of drug-laden contact lenses, development and classification of contact lenses, and features of the commonly used materials. A review of the methods commonly used in current research to create contact lenses has also been presented. An overview on how drug-laden contact lenses can overcome the problems of high burst and short release duration has been discussed. Overall, the review focuses on drug delivery methods using smart contact lenses, and predicts the future direction of research on contact lenses.
Priorities in Cardio-Oncology Basic and Translational Science
Authors: Fadi N. Salloum, Carlo G. Tocchetti, Pietro Ameri, Hossein Ardehali, Aarti Asnani, Rudolf A. de Boer, Paul Burridge, José-Ángel Cabrera, Javier de Castro, Raúl Córdoba, Ambra Costa, Susan Dent, Daniel Engelbertsen, María Fernández-Velasco, Mike Fradley, José J. Fuster, Carlos Galán-Arriola, Inés García-Lunar, Alessandra Ghigo, Anna González-Neira, Emilio Hirsch, Borja Ibáñez, Richard N. Kitsis, Suma Konety, Alexander R. Lyon, Pilar Martin, Adolfo G. Mauro, Manuel M. Mazo Vega, Wouter C. Meijers, Tomas G. Neilan, Tienush Rassaf, Melanie Ricke-Hoch, Pilar Sepulveda, Paaladinesh Thavendiranathan, Peter van der Meer, Valentin Fuster, Bonnie Ky, Teresa López-Fernández
Journal: JACC CardioOncology (2023)

Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.
AI-clinician collaboration via disagreement prediction: A decision pipeline and retrospective analysis of real-world radiologist-AI interactions
Authors: Morgan Sanchez, Kyle Alford, Viswesh Krishna, Thanh M. Huynh, Chanh D.T. Nguyen, Matthew P. Lungren, Steven Q.H. Truong, Pranav Rajpurkar
Journal: Cell Reports Medicine (2023)

Clinical decision support tools can improve diagnostic performance or reduce variability, but they are also subject to post-deployment underperformance. Although using AI in an assistive setting offsets many concerns with autonomous AI in medicine, systems that present all predictions equivalently fail to protect against key AI safety concerns. We design a decision pipeline that supports the diagnostic model with an ecosystem of models, integrating disagreement prediction, clinical significance categorization, and prediction quality modeling to guide prediction presentation. We characterize disagreement using data from a deployed chest X-ray interpretation aid and compare clinician burden in this proposed pipeline to the diagnostic model in isolation. The average disagreement rate is 6.5%, and the expected burden reduction is 4.8%, even if 5% of disagreements on urgent findings receive a second read. We conclude that, in our production setting, we can adequately balance risk mitigation with clinician burden if disagreement false positives are reduced.